Selective OX2R Antagonist May Be Promising for Insomnia

SEATTLE, WA—Further clinical investigation of the selective high affinity/potent dual orexin-2 receptor antagonist (OX2R) JNJ-42847922 is supported by preclinical and Phase 1 clinical data, a characterization of the agent presented at SLEEP 2015 has found.

The pharmacological properties of JNJ-42847922 were assessed in rodent models for efficacy in sleep promotion and in a preliminary Phase 1 study in healthy subjects, reported Christine Dugovic, PhD, Neuroscience, Janssen Research & Development, San Diego, CA.

She said that although various OX1/2R antagonists have been shown to promote sleep in animals and humans, “emerging preclinical data indicate that while selective blockade of OX2R is sufficient to initiate and prolong sleep, specificity of OX2R antagonists may favorably preserve physiological sleep.”

The effects of JNJ-42847922 on EEG sleep were tested in rats. The agent was administered at 3–30mg/kg orally, acute and 7-day repeated dosing, in OX2R knock-out (KO) and wild-type (WT) mice during the light or dark phase. Changes in nucleus accumbens dopamine levels were evaluated in rats by microdialysis.

Pharmacokinetic and safety profile in a single ascending dose study (morning dosing 10–80mg) was conducted in healthy males (ages 18–55), and sleepiness was assessed by the Stanford Sleepiness Scale.

The oral administration of JNJ-42847922 dose-dependently reduced NREM latency in rats and increased NREM sleep duration whereas REM sleep was minimally affected. In contrast to several dual OX1/2R antagonists, the REM/total sleep ratio was minimally altered. Efficacy was maintained upon 7-day repeated dosing and sleep returned to baseline level following discontinuation.

JNJ-42847922 similarly promoted sleep in WT mice but had no effect in OX2R KO mice. The compound did not increase dopamine release in rat nucleus accumbens nor produce place preference in mice, suggesting a lack of intrinsic motivational properties.

In healthy subjects, JNJ-42847922 showed a favorable pharmacokinetic and safety profile as well as a strong pharmacodynamic effect in the sleepiness rating. Findings from the study warrant further research in the treatment of insomnia, Dr. Dugovic added.